The Parameters Governing the Anti-Myopia Efficacy of Chromatically Simulated Myopic Defocus in Tree Shrews.

Purpose: We previously showed that exposing tree shrews (Tupaia belangeri, small diurnal mammals closely related to primates) to chromatically simulated myopic defocus (CSMD) counteracted small-cage myopia and instead induced hyperopia (approximately +4 diopters [D]). Here, we explored the parameters of this effect. Methods: Tree shrews were exposed to the following interventions for 11 days: (1) rearing in closed (n = 7) or open (n = 6) small cages; (2) exposed to a video display of Maltese cross images with CSMD combined with overhead lighting (n = 4); (3) exposed to a video display of Maltese cross images with zero blue contrast ("flat blue," n = 8); and (4) exposed to a video display of black and white grayscale tree images with different spatial filtering (blue pixels lowpass <1 and <2 cycles per degree [CPD]) for the CSMD. Results: (1) Tree shrews kept in closed cages, but not open cages, developed myopia. (2) Overhead illumination reduced the hyperopia induced by CSMD. (3) Zero-blue contrast produced hyperopia but slightly less than the CSMD. (4) Both of the CSMD tree images counteracted small cage myopia, but the one low pass filtering blue <1 CPD was more effective at inducing hyperopia. Conclusions: Any pattern with reduced blue contrast at and below approximately 1 CPD counteracts myopia/promotes hyperopia, but maximal effectiveness may require that the video display be the brightest object in the environment. Translational Relevance: Chromatically simulated myopic blur might be a powerful anti-myopia therapy in children, but the parameter selection could be critical. Issues for translation to humans are discussed.

Repeated Low-level Red-light Therapy: The Next Wave in Myopia Management?

SIGNIFICANCE: Exposure to long-wavelength light has been proposed as a potential intervention to slow myopia progression in children. This article provides an evidence-based review of the safety and myopia control efficacy of red light and discusses the potential mechanisms by which red light may work to slow childhood myopia progression.The spectral composition of the ambient light in the visual environment has powerful effects on eye growth and refractive development. Studies in mammalian and primate animal models (macaque monkeys and tree shrews) have shown that daily exposure to long-wavelength (red or amber) light promotes slower eye growth and hyperopia development and inhibits myopia induced by form deprivation or minus lens wear. Consistent with these results, several recent randomized controlled clinical trials in Chinese children have demonstrated that exposure to red light for 3 minutes twice a day significantly reduces myopia progression and axial elongation. These findings have collectively provided strong evidence for the potential of using red light as a myopia control intervention in clinical practice. However, several questions remain unanswered. In this article, we review the current evidence on the safety and efficacy of red light as a myopia control intervention, describe potential mechanisms, and discuss some key unresolved issues that require consideration before red light can be broadly translated into myopia control in children.

The effects of ambient narrowband long-wavelength light on lens-induced myopia and form-deprivation myopia in tree shrews.

Here we examine the effects of ambient red light on lens-induced myopia and diffuser-induced myopia in tree shrews, small diurnal mammals closely related to primates. Starting at 24 days of visual experience (DVE), seventeen tree shrews were reared in red light (624 ± 10 or 634 ± 10 nm, 527-749 human lux) for 12-14 days wearing either a -5D lens (RL-5D, n = 5) or a diffuser (RLFD, n = 5) monocularly, or without visual restriction (RL-Control, n = 7). Refractive errors and ocular dimensions were compared to those obtained from tree shrews raised in broad-spectrum white light (WL-5D, n = 5; WLFD, n = 10; WL Control, n = 7). The RL-5D tree shrews developed less myopia in their lens-treated eyes than WL-5D tree shrews at the end of the experiment (-1.1 ± 0.9D vs. -3.8 ± 0.3D, p = 0.007). The diffuser-treated eyes of the RLFD tree shrews were near-emmetropic (-0.3 ± 0.6D, vs. -5.4 ± 0.7D in the WLFD group). Red light induced hyperopia in control animals (RL-vs. WL-Control, +3.0 ± 0.7 vs. +1.0 ± 0.2D, p = 0.02), the no-lens eyes of the RL-5D animals, and the no-diffuser eyes of the RLFD animals (+2.5 ± 0.5D and +2.3 ± 0.3D, respectively). The refractive alterations were consistent with the alterations in vitreous chamber depth. The lens-induced myopia developed in red light suggests that a non-chromatic cue could signal defocus to a less accurate extent, although it could also be a result of "form-deprivation" caused by defocus blur. As with previous studies in rhesus monkeys, the ability of red light to promote hyperopia appears to correlate with its ability to retard lens-induced myopia and form-deprivation myopia, the latter of which might be related to non-visual ocular mechanisms.

The effects of intensity, spectral purity and duty cycle on red light-induced hyperopia in tree shrews.

INTRODUCTION: There have recently been several clinical studies suggesting that brief periods of exposure to red light (repeated low-level red light, 'RLRL') may produce a dramatic anti-myopia effect, calling for further investigations into its therapeutic parameters. Unfortunately, many experimental species used in refractive studies develop myopia in response to this wavelength. Tree shrews are the only animal model other than rhesus monkeys that consistently exhibit hyperopic responses to ambient red light. Here, tree shrews were used to study the influence of the spectral purity, duty cycle and intensity of red light on its anti-myopic effect. METHODS: Juvenile tree shrews (Tupaia belangeri) were raised from 24 to 35 days after eye opening under ambient lighting that was: standard white colony fluorescent light; pure narrow band red light of either 600, 50-100 or 5 lux; red light that was diluted with 10% white light (by lux) or 50% white and 2 s of pure red light that alternated with 2 s of pure white light (50% duty cycle). Refractive measures were taken with a NIDEK ARK-700 autorefractor and axial dimensions with a LenStar LS-900 Axial Biometer. RESULTS: The pro-hyperopia effect of ambient red light was greatly reduced by even small amounts of concurrent white light 'contamination', but remained robust if 2-s periods of pure white light alternated with 2 s of red. Finally, the hyperopic effect of red light was maintained at reduced luminance levels in the 50-100 lux range and only failed at 5 lux. CONCLUSIONS: These results have implications for understanding the mechanisms by which ambient red light affects refractive development, and possibly also for clinical therapies using RLRL. Nevertheless, it remains to be determined if the mechanism of the current clinical RLRL therapy is the same as that operating on tree shrews in ambient red light.

IMI 2023 Digest.

Myopia is a dynamic and rapidly moving field, with ongoing research providing a better understanding of the etiology leading to novel myopia control strategies. In 2019, the International Myopia Institute (IMI) assembled and published a series of white papers across relevant topics and updated the evidence with a digest in 2021. Here, we summarize findings across key topics from the previous 2 years. Studies in animal models have continued to explore how wavelength and intensity of light influence eye growth and have examined new pharmacologic agents and scleral cross-linking as potential strategies for slowing myopia. In children, the term premyopia is gaining interest with increased attention to early implementation of myopia control. Most studies use the IMI definitions of ≤-0.5 diopters (D) for myopia and ≤-6.0 D for high myopia, although categorization and definitions for structural consequences of high myopia remain an issue. Clinical trials have demonstrated that newer spectacle lens designs incorporating multiple segments, lenslets, or diffusion optics exhibit good efficacy. Clinical considerations and factors influencing efficacy for soft multifocal contact lenses and orthokeratology are discussed. Topical atropine remains the only widely accessible pharmacologic treatment. Rebound observed with higher concentration of atropine is not evident with lower concentrations or optical interventions. Overall, myopia control treatments show little adverse effect on visual function and appear generally safe, with longer wear times and combination therapies maximizing outcomes. An emerging category of light-based therapies for children requires comprehensive safety data to enable risk versus benefit analysis. Given the success of myopia control strategies, the ethics of including a control arm in clinical trials is heavily debated. IMI recommendations for clinical trial protocols are discussed.

Fighting Myopia with Intermittent Nearwork Breaks: 20 Seconds Every 20 Minutes Might Not Be Enough Time.

SIGNIFICANCE: Practitioners commonly prescribe the 20/20/20 rule with hopes that, if patients follow it, they will reduce their myopic progression. This clinical perspective provides evidence that 20-second break from nearwork every 20 minutes are not enough time to impact ocular growth.The ongoing myopia epidemic is a major public health crisis. Although the correlation between nearwork tasks such as reading, computers, and smartphones and myopia development is controversial, multiple lines of research suggest that sustained nearwork contributes to myopia development. Clinicians have proposed that children should take short breaks from nearwork with a 20-second break every 20 minutes being a common suggestion. Animal model data do strongly support the idea that multiple short breaks across time can cancel out the effects of longer periods of myopia-promoting activities. However, the animal model data also suggest that repeated episodes of 20 seconds are ineffective at reducing myopia development and instead indicate that sustained breaks of 5 minutes or more every hour are needed to negate myopiagenic effects.

Limited bandwidth short-wavelength light produces slowly-developing myopia in tree shrews similar to human juvenile-onset myopia.

During postnatal development, an emmetropization feedback mechanism uses visual cues to modulate the axial growth of eyes so that, with maturation, images of distant objects are in focus on the retina. If the visual cues indicate that the eye has become too long, it generates STOP signals that slow eye elongation. Myopia is a failure of this process where the eye becomes too long. The existing animal models of myopia have been essential in understanding the mechanics of emmetropization but use visual cues that lead to rapidly progressing myopia and don't match the stimuli that lead to human myopia. Form deprivation removes esssentially all spatial contrast. Minus lens wear accurately guides axial elongation to restore sharp focus: technically it is not a model of myopia! In contrast, childhood myopia involves a slow drift into myopia, even with the presence of clear images. We hypothesize that, in the modern visual environment, STOP signals are present but often are not quite strong enough to prevent myopic progression. Using tree shrews, small diurnal mammals closely related to primates, we have developed an animal model that we propose better represents this situation. We used limited bandwidth light to provide limited chromatic cues for emmetropization that are not quite enough to produce fully effective STOP signaling, resulting in a slow drift into myopia as seen in children. We hypothesize that this animal model of myopia may prove useful in evaluating anti-myopia therapies where form deprivation and minus lens wear would be too powerful.

Chromatically simulated myopic blur counteracts a myopiagenic environment.

There is a world-wide epidemic of myopia (nearsightedness), produced largely by human-made environmental visual cues that disrupt the emmetropization feedback mechanism that normally uses defocus cues to produce and maintain eyes in good focus. Previous studies have shown that the wavelength of light affects this process and that myopic defocus can slow the progression of myopia in children. We first asked if continuous exposure to a small cage with restricted viewing distance would produce an environmentally-induced myopia in tree shrews, small diurnal mammals closely related to primates. A group (n = 7) spent 11 days in a small cage with restricted viewing distance; one wall was a video display covered with Maltese crosses that included low-to-high spatial frequencies in the range visible to tree shrews. This group developed myopia (-1.2 ± 0.4 [stderr] D) that was significant relative to a colony group of seven animals (+1.0 ± 0.2 D) raised in mesh cages allowing more distant viewing. We then asked if chromatically-simulated myopic defocus, produced by blurring just the blue channel of the video display, would counteract this environmentally-induced myopia in a group of eight tree shrews. This group instead became significantly hyperopic (+4.0 ± 0.4 D) due to slowed axial elongation. These results demonstrate the high potency of chromatic cues in refractive regulation and may provide the basis for an anti-myopia treatment in humans.

A multimodal neuroimaging study investigating resting-state connectivity, glutamate and GABA at 7 T in first-episode psychosis.

BACKGROUND: The major excitatory and inhibitory neurometabolites in the brain, glutamate and γ-aminobutyric acid (GABA), respectively, are related to the functional MRI signal. Disruption of resting-state functional MRI signals has been reported in psychosis spectrum disorders, but few studies have investigated the role of these metabolites in this context. METHODS: We included 19 patients with first-episode psychosis and 21 healthy controls in this combined magnetic resonance spectroscopy (MRS) and resting-state functional connectivity study. All imaging was performed on a Siemens Magnetom 7 T MRI scanner. Both the MRS voxel and the seed for functional connectivity analysis were located in the dorsal anterior cingulate cortex (ACC). We used multiple regressions to test for an interaction between ACC brain connectivity, diagnosis and neurometabolites. RESULTS: ACC brain connectivity was altered in first-episode psychosis. The relationship between ACC glutamate and ACC functional connectivity differed between patients with first-episode psychosis and healthy controls in the precuneus, retrosplenial cortex, supramarginal gyrus and angular gyrus. As well, the relationship between ACC GABA and ACC functional connectivity differed between groups in the caudate, putamen and supramarginal gyrus. LIMITATIONS: We used a small sample size. As well, although they were not chronically medicated, all participants were medicated during the study. CONCLUSION: We demonstrated a link between the major excitatory and inhibitory brain metabolites and resting-state functional connectivity in healthy participants, as well as an alteration in this relationship in patients with first-episode psychosis. Combining data from different imaging modalities may help our mechanistic understanding of the relationship between major neurometabolites and brain network dynamics, and shed light on the pathophysiology of first-episode psychosis.

Amber light treatment produces hyperopia in tree shrews.

PURPOSE: Exposure to narrow-band red light, which stimulates only the long-wavelength sensitive (LWS) cones, slows axial eye growth and produces hyperopia in tree shrews and macaque monkeys. We asked whether exposure to amber light, which also stimulates only the LWS cones but with a greater effective illuminance than red light, has a similar hyperopia-inducing effect in tree shrews. METHODS: Starting at 24 ± 1 days of visual experience, 15 tree shrews (dichromatic mammals closely related to primates) received light treatment through amber filters (BPI 500/550 dyed acrylic) either atop the cage (Filter group, n = 8, 300-400 human lux) or fitted into goggles in front of both eyes (Goggle group, n = 7). Non-cycloplegic refractive error and axial ocular dimensions were measured daily. Treatment groups were compared with age-matched animals (Colony group, n = 7) raised in standard colony fluorescent lighting (100-300 lux). RESULTS: At the start of treatment, mean refractive errors were well-matched across the three groups (p = 0.35). During treatment, the Filter group became progressively more hyperopic with age (p < 0.001). By contrast, the Goggle and Colony groups showed continued normal emmetropization. When the treatment ended, the Filter group exhibited significantly greater hyperopia (mean [SE] = 3.5 [0.6] D) compared with the Goggle (0.2 [0.8] D, p = 0.01) and Colony groups (1.0 [0.2] D, p = 0.01). However, the refractive error in the Goggle group was not different from that in the Colony group (p = 0.35). Changes in the vitreous chamber were consistent with the refractive error changes. CONCLUSIONS: Exposure to ambient amber light produced substantial hyperopia in the Filter group but had no effect on refractive error in the Goggle group. The lack of effect in the Goggle group could be due to the simultaneous activation of the short-wavelength sensitive (SWS) and LWS cones caused by the scattering of the broad-band light from the periphery of the goggles.

How chromatic cues can guide human eye growth to achieve good focus.

The postnatal growing eye uses visual cues to actively control its own axial elongation to achieve and maintain sharp focus, a process termed emmetropization. The primary visual cue may be the difference in image sharpness as sensed by the arrays of short- and long-wavelength sensitive cone photoreceptors caused by longitudinal chromatic aberration: Shorter wavelengths focus in front of longer wavelengths. However, the sparse distribution of short-wavelength sensitive cones across the retina suggests that they do not have sufficient spatial sampling resolution for this task. Here, we show that the spacing of the short-wavelength sensitive cones in humans is sufficient for them, in conjunction with the longer wavelength cones, to use chromatic signals to detect defocus and guide emmetropization. We hypothesize that the retinal spacing of the short-wavelength sensitive cones in many mammalian species is an evolutionarily ancient adaption that allows the efficient use of chromatic cues in emmetropization.

Effect of Scleral Crosslinking Using Multiple Doses of Genipin on Experimental Progressive Myopia in Tree Shrews.

Purpose: To evaluate the effect of scleral crosslinking (SXL) on slowing experimental progressive myopia in tree shrew eyes using sub-Tenon's injections of genipin (GEN) at different concentrations and number of injections. Methods: Three or five sub-Tenon's injections of GEN at 0 mM (sham), 10 mM, or 20 mM were performed in one eye every other day starting at 18 days of visual experience. Form deprivation (FD) myopia was induced in the injected eye between 24 and 35 days of visual experience; the fellow eye served as control. Tree shrews were randomly assigned to five experimental groups: FD (n = 8); FD + 5 × sham injections (n = 6); FD + 3 × GEN injections at 10 mM (n = 6) and 20 mM (n = 6); and FD + 5 × GEN injections at 20 mM (n = 6). Refractive state and ocular dimensions were measured daily. Results: Compared with the FD group, the sham-injected group showed a transient effect on slowing vitreous chamber elongation. With increasing GEN dose, SXL had an increasing treatment effect on slowing vitreous chamber elongation and myopia progression. In addition, SXL led to a dose-dependent shortening of the aqueous chamber depth and corneal thickening. Lens thickening was observed in the group with the highest concentration. Conclusions: We have shown that SXL using GEN can slow axial elongation and myopia progression in tree shrews. The extent of this treatment effect was dose dependent. Several unexpected effects were observed (corneal thickening, decrease of the anterior chamber depth, and lens thickening), which require further optimization of the GEN delivery approach before clinical consideration. Translational Relevance: The results of this preclinical study suggest that scleral crosslinking using genipin can slow myopia progression.

Tree shrews do not maintain emmetropia in initially-focused narrow-band cyan light.

We asked if emmetropia, achieved in broadband colony lighting, is maintained in narrow-band cyan light that is well focused in the emmetropic eye, but does not allow for guidance from longitudinal chromatic aberrations (LCA) and offers minimal perceptual color cues. In addition, we examined the response to a -5 D lens in this lighting. Seven tree shrews from different litters were initially housed in broad-spectrum colony lighting. At 24 ± 1 days after eye opening (Days of Visual Experience, DVE) they were housed for 11 days in ambient narrow-band cyan light (peak wavelength 505 ± 17 nm) selected because it is in focus in an emmetropic eye. Perceptually, monochromatic light at 505 nm cannot be distinguished from white by tree shrews. While in cyan light, each animal wore a monocular -5 D lens (Cyan -5 D eyes). The fellow eye was the Cyan no-lens eye. Daily awake non-cycloplegic measures were taken with an autorefractor (refractive state) and with optical low-coherence optical interferometry (axial component dimensions). These measures were compared with the values of animals raised in standard colony fluorescent lighting: an untreated group (n = 7), groups with monocular form deprivation (n = 7) or monocular -5 D lens treatment (n = 5), or that experienced 10 days in total darkness (n = 5). Refractive state at the onset of cyan light treatment was low hyperopia, (mean ± SEM) 1.4 ± 0.4 diopters. During treatment, the Cyan no-lens eyes became myopic (-2.9 ± 0.3 D) whereas colony lighting animals remained slightly hyperopic (1.0 ± 0.2 D). Initially, refractions of the Cyan -5 D eyes paralleled the Cyan no-lens eyes. After six days, they gradually became more myopic than the Cyan no-lens eyes; at the end of treatment, the refractions were -5.4 ± 0.3 D, a difference of -2.5 D from the Cyan no-lens eyes. When returned to colony lighting at 35 ± 1 DVE, the no-lens eye refractions rapidly recovered towards emmetropia but, as expected, the refraction of the -5 D eyes remained near -5 D. Vitreous chamber depth in both eyes was consistent with the refractive changes. In narrow-band cyan lighting the emmetropization mechanism did not maintain emmetropia even though the light initially was well focused. We suggest that, as the eyes diverged from emmetropia, there were insufficient LCA cues for the emmetropization mechanism to utilize the developing myopic refractive error in order to guide the eyes back to emmetropia. However, the increased myopia in the Cyan -5 D eyes in the narrow-band light indicates that the emmetropization mechanism nonetheless detected the presence of the lens-induced refractive error and responded with increased axial elongation that partly compensated for the negative-power lens. These data support the conclusion that the emmetropization mechanism cannot maintain emmetropia in narrow-band lighting. The additional myopia produced in eyes with the -5 D lens shows that the emmetropization mechanism responds to multiple defocus-related cues, even under conditions where it is unable to use them to maintain emmetropia.

A multimodal magnetoencephalography 7 T fMRI and 7 T proton MR spectroscopy study in first episode psychosis.

We combined magnetoencephalography (MEG), 7 T proton magnetic resonance spectroscopy (MRS), and 7 T fMRI during performance of a task in a group of 23 first episode psychosis (FEP) patients and 26 matched healthy controls (HC). We recorded both the auditory evoked response to 40 Hz tone clicks and the resting state in MEG. Neurometabolite levels were obtained from the anterior cingulate cortex (ACC). The fMRI BOLD response was obtained during the Stroop inhibitory control task. FEP showed a significant increase in resting state low frequency theta activity (p < 0.05; Cohen d = 0.69), but no significant difference in the 40 Hz auditory evoked response compared to HC. An across-groups whole brain analysis of the fMRI BOLD response identified eight regions that were significantly activated during task performance (p < 0.01, FDR-corrected); the mean signal extracted from those regions was significantly different between the groups (p = 0.0006; d = 1.19). In the combined FEP and HC group, there was a significant correlation between the BOLD signal during task performance and MEG resting state low frequency activity (p < 0.05). In FEP, we report significant alteration in resting state low frequency MEG activity, but no alterations in auditory evoked gamma band response, suggesting that the former is a more robust biomarker of early psychosis. There were no correlations between gamma oscillations and GABA levels in either HC or FEP. Finally, in this study, each of the three imaging modalities differentiated FEP from HC; fMRI with good and MEG and MRS with moderate effect size.

An opponent dual-detector spectral drive model of emmetropization.

In post-natal developing eyes a feedback mechanism uses optical cues to regulate axial growth so as to achieve good focus, a process termed emmetropization. However, the optical cues that the feedback mechanism uses have remained unclear. Here we present evidence that a primary visual cue may be the detection of different image statistics by the short-wavelength sensitive (SWS) and long-wavelength sensitive (LWS) cone photoreceptors, caused by longitudinal chromatic aberration (LCA). We use as a model system the northern tree shrew Tupaia belangeri, diurnal cone-dominated dichromatic mammals closely related to primates. We present an optical model in which the SWS and LWS photoreceptors each represent an image at different levels of defocus. The model posits that an imbalance between SWS and LWS image statistics directs eye growth towards the point at which these image statistics are in balance. Under spectrally broadband ("white") lighting, the focus of the eye is driven to a target point approximately in the middle of the visible spectrum, which is emmetropia. Calculations suggest that the SWS cone array, despite the sparse number of SWS cones, can plausibly detect the wavelength-dependent differences in defocus and guide refractive development. The model is consistent with the effects of various narrow-band illuminants on emmetropization in tree shrews. Simulations suggest that common artificial light spectra do not interfere with emmetropization. Simulations also suggest that multi-spectral multi-focal lenses, where the different optical zones of a multifocal lens have different spectral filtering properties, could be an anti-myopia intervention.

Examining resting-state functional connectivity in first-episode schizophrenia with 7T fMRI and MEG.

Schizophrenia is often characterized by dysconnections in the brain, which can be estimated via functional connectivity analyses. Commonly measured using resting-state functional magnetic resonance imaging (fMRI) in order to characterize the intrinsic or baseline function of the brain, fMRI functional connectivity has significantly contributed to the understanding of schizophrenia. However, these measures may not capture the full extent of functional connectivity abnormalities in schizophrenia as fMRI is temporally limited by the hemodynamic response. In order to extend fMRI functional connectivity findings, the complementary modality of magnetoencephalography (MEG) can be utilized to capture electrophysiological functional connectivity abnormalities in schizophrenia that are not obtainable with fMRI. Therefore, we implemented a multimodal functional connectivity analysis using resting-state 7 Tesla fMRI and MEG data in a sample of first-episode patients with schizophrenia (n = 19) and healthy controls (n = 24). fMRI and MEG data were decomposed into components reflecting resting state networks using a group spatial independent component analysis. Functional connectivity between resting-state networks was computed and group differences were observed. In fMRI, patients demonstrated hyperconnectivity between subcortical and auditory networks, as well as hypoconnectivity between interhemispheric homotopic sensorimotor network components. In MEG, patients demonstrated hypoconnectivity between sensorimotor and task positive networks in the delta frequency band. Results not only support the dysconnectivity hypothesis of schizophrenia, but also suggest the importance of jointly examining multimodal neuroimaging data as critical disorder-related information may not be detectable in a single modality alone.

7T Proton Magnetic Resonance Spectroscopy of the Anterior Cingulate Cortex in First-Episode Schizophrenia.

Recent magnetic resonance spectroscopy (MRS) studies suggest that abnormalities of the glutamatergic system in schizophrenia may be dependent on illness stage, medication status, and symptomatology. Glutamatergic metabolites appear to be elevated in the prodromal and early stages of schizophrenia but unchanged or reduced below normal in chronic, medicated patients. However, few of these studies have measured metabolites with high-field 7T MR scanners, which offer higher signal-to-noise ratio and better spectral resolution than 3T scanners and facilitate separation of glutamate and glutamine into distinct signals. In this study, we examined glutamate and other metabolites in the dorsal anterior cingulate cortex (ACC) of first-episode schizophrenia patients. Glutamate and N-acetylaspartate (NAA) were significantly lower in schizophrenia patients vs controls. No differences were observed in levels of glutamine, GABA, or other metabolites. In schizophrenia patients but not controls, GABA was negatively correlated with the total score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as well as the immediate memory and language subscales. Our findings suggest that glutamate and NAA reductions in the ACC may be present early in the illness, but additional large-scale studies are needed to confirm these results as well as longitudinal studies to determine the effect of illness progression and treatment. The correlation between GABA and cognitive function suggests that MRS may be an important technique for investigating the neurobiology underlying cognitive deficits in schizophrenia.

Relationship Between Cortical Excitation and Inhibition and Task-Induced Activation and Deactivation: A Combined Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study at 7T in First-Episode Psychosis.

BACKGROUND: Schizophrenia is thought to be a disorder of brain dysconnectivity. An imbalance between cortical excitation/inhibition is also implicated, but the link between these abnormalities remains unclear. The present study used magnetic resonance spectroscopy and functional magnetic resonance imaging at 7T to investigate how measurements of glutamate and gamma-aminobutyric acid (GABA) relate to the blood oxygen level-dependent (BOLD) response during a cognitive task, and how these relationships are altered in schizophrenia. METHODS: Usable functional magnetic resonance imaging data from 17 first-episode psychosis (FEP) patients (4 women, 13 men) and 21 matched healthy control subjects (HCs) (5 women, 16 men) were acquired during a Stroop task. Within- and between-group comparisons of the BOLD response were performed. Neurometabolite levels were measured in the dorsal anterior cingulate cortex. Two multiple regressions investigated how glutamate, glutamine, and GABA related to the BOLD response in HCs and FEP patients separately. A third investigated between-group differences in the relationships between the BOLD response and each of these neurometabolites. RESULTS: Compared with HCs, FEP patients showed an increased BOLD response within regions of the executive and default mode networks. In FEP patients, the relationship between anterior cingulate cortex glutamate levels and the BOLD response in regions of the posterior default mode network was opposite to that of HCs. In FEP patients but not HCs, anterior cingulate cortex GABA levels correlated with the local BOLD response and with the Stroop reaction time. CONCLUSION: These results suggest a mechanism whereby alterations in the relationship between cortical glutamate/GABA and BOLD response is disrupting the dynamic of major neural networks, possibly affecting cognition.